Major Depressive Disorder and Their Key Characteristics - Coursework Example

Major Depressive Disorder Introduction Major depression disorder or MDD or unipolar depression or clinical depression is a common mental illnessthat falls into the category of mood disorders. It can cause significant impairment in social functioning, role functioning, employment and physical health of the afflicted person (Wells et al, 1989). Though many effective treatments are available, this common psychiatric illness is frequently under diagnosed and improperly treated (Bhalla & Aronson, 2006). Definition and clinical presentation According to the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders (DSM) IV TR, 2000, diagnosis of MDD is made as follows (Nestler et al 2002; Bhalla & Aronson, 2006): 1. When a certain number of depression symptoms as mentioned below are reported for longer than 2 week period of time, and when the symptoms disrupt normal social and occupational functioning, then a diagnosis of MDD is made. 2. The symptoms of depression which are considered for diagnosis are depressed mood, irritability, low self esteem, feelings of hopelessness, worthlessness, and guilt, decreased ability to concentrate and think, decreased or increased appetite, weight loss or weight gain, insomnia or hypersomnia, low energy, fatigue, or increased agitation, decreased interest in pleasurable stimuli (e.g., sex, food, social interactions) and recurrent thoughts of death and suicide. 3. The symptoms must not meet criteria for both manic and depressive episodes 4. The symptoms must not be direct effects of any physiological state, substance intake or medical condition. Atypical presentations Primary care health professionals must be aware of the fact that some MDD patients may initially present with somatic symptoms like fatigue, headache, abdominal distress, or change in weight or subtle symptoms like irritability (Bhalla & Aronson, 2006). Older persons may present with confusion or a general decline in functioning and hence may go unnoticed (Bhalla & Aronson, 2006). In children, manifestations of MDD can be symptoms like irritability, decline in school performance, or social withdrawal (Bhalla & Aronson, 2006). Differential diagnosis MDD has to be differentiated from mood disorders secondary to CNS conditions. Alzheimer disease and other degenerative and vascular dementias can be associated with affective symptoms of depression. Symptoms of depression are also common in Parkinson disease, Huntington disease, multiple sclerosis, stroke, seizure disorders, CNS tumors and sleep disorders. Obstructive sleep apnea can cause significant medical and psychiatric symptoms. The diagnosis of this cause is evident by enquiring family members. Addison disease, Cushing disease, hyperthyroidism, hypothyroidism, prolactinomas, and hyperparathyroidism are some of the endocrine disorders known to cause MDD. Certain infections like HIV encepahalopathy and Lyme disease may mimic MDD. Some medications like beta blockers, reserpine, sex hormones and chemotherapy have mood alteration properties and symptoms may mimic MDD. Also, illicit substances have mood-altering properties (Bhalla & Aronson, 2006). Certain psychiatric diseases also are known to be comorbid with MDD. Comorbid depression is common in those with anxiety disorder. Dysthymia can initially present with low mood. MDD is also comornid with certain eating disorders like bulimia and anorexia nervosa and some personality disorders (Bhalla & Aronson, 2006). Incidence and prevalence In the United States, the lifetime incidence of MDD has been estimated as 20% in women and 12% in men (Bhalla & Aronson, 2006). In general, according to the National Comorbidity Survey Replication (NCS-R), which studied the epidemiology of MDD across the United States, the prevalence of MDD for lifetime was estimated as 16.2% and that for 12-month was estimated as 6.6% (Kessler et al, 2003). Severe forms of depression affect 2-5% of the US population (Nestler et al, 2002). One important aspect of the prevalence of MDD is that there are cultural and racial influences on the disease presentation. Depression is less common in the black population (Bhalla & Aronson, 2006). There are not many studies estimating the prevalence of MDD across various races and cultures. A study by Williams et al (2007) estimated the lifetime MDD prevalence in the whites as 17.9%, followed by Caribbean blacks (12.9%) and African Americans (10.4%). However, the researchers concluded that 12-month MDD estimates across these groups were similar. MDD can develop at any age. But the risk is low in younger age. The mean age of onset is 32 (Kessler et al, 2005). Mortality and morbidity MDD is associated with significant amount of mortality and morbidity. It contributes to suicide, medical illness like myocardial infarction, disruption in interpersonal relationships, substance abuse, and lost work time (Bhalla & Aronson, 2006). MDD plays a role in more than one half of all suicide attempts (Bhalla & Aronson, 2006). Etiology and pathogenesis Multiple etiologies have been described in the pathogenesis of MDD which involves genetic and non-genetic risk factors. Environmental and psychosocial factors: Viral infections, reduced omega-2 fatty acids in diet, stress, reduced sleep, emotions and insults during brain development (Nestler et al, 2002) have been implicated in the etiology of depression. Some of the medical conditions which cause depression are endocrine disorders, collagen vascular diseases, Parkinson’s disease, head injury, certain cancers, asthma, diabetes and stroke (Nestler et al, 2002). Some researchers attribute even trivial brain injury (Rapoport et al, 2003) and mass disaster (Person et al, 2006) to MDD. Exposure to marijuana (Leech et al, 2006) and smoking (Gray at al, 2005) during gestation can also lead to depressive symptoms later in life. Neuroanatomical changes: Studies on animal models inflicted with mental illness have shown various changes in the brain. These changes include differences in the sizes of specific regions in the brain, changes in the morphological aspects of some of the subpopulations of neurons and neurochemical changes at the synaptic cleft (Tsankova et al, 2007). Also, alterations in intracellular signaling and changes in the regulation of gene expression have also been noted. Hippocampus (Tsankova et al, 2007) and prefrontal cortex region (Schatzberg, 2002) are the specific brain regions which have been implicated in the pathogenesis of MDD. The volume of hippocampus is decreased in patients with MDD and this has been attributed to the excessive glucocorticoid activity (Schatzberg, 2002). Hippocampus is the center for mood and memory and prefrontal cortex is the center for cognition. Hence pathological affectation in these regions of brain contributes to the somatic and cognitive symptoms of the disorder (Schatzberg, 2002). Some researchers have attributed the symptoms of MDD to regional blood flow changes. Drevets (2000) associated some symptoms of MDD to focal abnormalities of regional cerebral blood flow in regions like orbital and medial prefrontal cortex, the amygdala, and related parts of the striatum and thalamus. The symptoms he studied were cognitive deficits, psychomotor retardation, anhedonia, and lowered mood. Graff et al (2007) proved that cerebral blood flow before anti depressant therapy (ADT) increases in brain areas like right temporal gyrus, left amygdale, right anterior cingulated cortex, bilateral medial frontal gyrus, bilateral insula, lingual gyrus, right precentral gyrus and left postcentral gyrus.related with the affective and cognitive components of pain; in contrast, after ADT increases only in cognitive pain related areas. Bowley et al (2002) demonstrated low glial density and reduced glia/neuron ratio in these areas. Other than hippocampus and prefontal cortex, hypothalamus and nucleus accumbens have also been shown to be involved in the pathogenesis (Nestler et al, 2002). Symptoms related to appetite, sleep and circadian rhythm can be attributed to pathology in these regions. The neural circuits between these pathological areas in the brain is said to contribute to the symptoms. Affectation of dopaminergic neurons in the ventral tegmental area and nucleus acumens is said to cause anhedonia and decreased motivation (Berton and Nestley, 2006). Neuroendocrine changes: Neuroendocrine changes in some regions of the brain have been attributed to symptoms of MDD. The most common theory is prolonged levels of glucocorticosteroids due to chronic stress. Prolonged elevation of these hormones can damage hippocampal neurons especially the CA3 pyramidal neurons (Nestler et al, 2002) leading to reduction in the inhibitory control of hippocampus on the Hypothalamic-Pituitary-Adrenal axis. This reduction in the inhibitory control of hippocampus further increases the steroid production in the body and it further damages the hippocampus. Some researchers have proposed that impaired functioning of the glucocorticoid receptors is the cause for steroid resistance and that this may contribute to excessive inflammation as well as hyperactivity of corticotropin releasing hormone and sympathetic nervous system pathways. These changes have been attributed to the symptoms of MDD. What causes glucocorticosteroid resistance is not known. Some have attributed this to chronic exposure to inflammatory cytokines as may occur during chronic medical illness or chronic stress (Pace et al, 2007). While hypercortisolemia is not universal in depression, but among those depressed subjects with hypercortisolemia, these physiological abnormalities can disappear after successful clinical intervention (Sheps and Rozanski, 2005). Another theory proposed is hippocampal neurogenesis. Neurotropic support is essential for neural growth and development and currently neurotropic factors are considered as potent regulators of plasticity and survival of adult neurons and glia (Nestler et al, 2002). Thus, deficiency of neurotropic support leads to symptoms of MDD. Other than glucocorticosteroids, sympathetic hormones also have a role in the etiology of MDD. Depression is sometimes associated with stimulation of the sympathetic nervous system resulting in elevated levels of circulating plasma norepinephrine levels. This is supported by the fact that depressed subjects generally manifest increases in resting heart rates compared with non depressed controls (Sheps and Rozanski, 2005). Neurochemical changes: Some researchers have proposed that certain chemical imbalances in the brain cause clinical symptoms in MDD. These imbalances are said to occur in certain neurotransmitters like serotonin, noradrenaline and dopamine (Bourin et al, 2002). It is not clear as to how these chemicals cause symptoms in MDD. Altered glucose metabolism is one of the proposed theories. Positron Emission (PET) studies have proved the relationship of altered glucose metabolism with respect to serotonin imbalances in MDD (Anderson et al, 2003). Kumar et al, 1993 and Sackeim et al, 1993 have demonstrated lower levels of glucose metabolism and cerebral blood flow in neocortical and subcortical regions in elderly patients with MDD. Recent researchers argue that it is the problem in information processing within neural networks, rather than changes in chemical balance that causes symptoms (Castren, 2005). Genetic factors: The most widely accepted etiology to depression is genetic factor. Studies have shown that 40-50% of the risk for depression is genetic (Nestler et al, 2002). However, no single gene has been attributed to this so far probably because of the possibility of many genes involved in a complex manner (Nestler et al, 2002). Some researchers argue that the early onset type of MDD has more genetic relation. In certain families, there is preliminary evidence that recurrent, early-onset major depression is linked to a region containing the CREB1 gene (Hasler et al, 2004). This is because CREB1 plays major roles in neuronal plasticity, cognition, and memory. Kendler et al (1999) reported that intermediate levels of recurrence of depressive episodes and recurrent thoughts of death and suicide are associated with high genetic liability of MDD and are specific characteristic of familial MDD. It has been reported that CAG repeats length and alleles distributions in the androgen receptor gene in men with MDD are different from those without MDD; hence there is a possibility that AR gene might be involved in the depressive upset in adolescents (Su et al, 2007). Epigenetic factors: The most recent research in the pathogenesis of MDD is the role of epigenetic mechanisms. Epigenetic mechanisms are those mechanisms which exert lasting control over gene expression without altering the genetic code by means of enzyme modifications to chromatin structure that can upregulate or downregulate gene expression in a manner that is transmissible to daughter cells and also regulate gene expression in neurons making chromatin modifications sustain within individual cells (Tsankova et al, 2007). To define the causative factor of this mechanism, the term endophyte was coined. Endophyte has been described as an internal phenotype that fills the gap between available descriptors and between the gene and the elusive disease process and therefore may help to resolve questions about etiological models (Hasler et al, 2004). Treatment of MDD Evidence-based treatment guidelines are limited in MDD (Bhalla & Aronson, 2006). Both pharmaco therapies and psychotherapies are in vogue to treat MDD. Psychotherapies are given in milder, uncomplicated, non-chronic cases of MDD. Also, those who respond to medication are converted to remitters using psychotherapies (Rush and Thase, 2001). The drugs which are used in the treatment of MDD are known as anti-depressants and all these drugs act via monoamine neurotransmitters serotonin or noradrenaline. They induce plastic changes in neuronal connectivity, which gradually lead to improvements in neuronal information processing and recovery of mood (Castren, 2005). They need to be given for several weeks for effectiveness and in the course, there is high potential for side effects like serotonin syndrome and over dose deaths (Kapur et al, 1992). Many of the unwanted side effects are due to the fact that the drugs, especially the tricyclic anti-depressants and monoamine oxidase inhibitors also block histaminic, cholinergic, and alpha1-adrenergic receptor sites which lead to side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness (Feighner, 1999). The remission rate is only 50% (Berteno and Nestler, 2006). They need to be continued for about 1 to 5 years after remission has been achieved (Nemeroff, 1994). Antidepressant drugs are classified according to their ability to improve monoaminergic transmission (Refer to table-1). They are basically classified as: tricyclics, selective serotonin reuptake inhibitors, noradrenaline reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, monoamine oxidase inhibitors and others (lithium and atypical antidepressants) (Bertono & Nestler, 2006) Type of treatment Mode of action Examples Medication Tricyclics Selective serotonin reuptake inhibitors (SSRIs) Noradrenaline reuptake inhibitors (NRIs) Serotonin and noradrenaline reuptake inhibitors (SNRIs) Monoamine oxidase inhibitors MAOIs) Lithium Atypical antidepressants Inhibition of mixed noradrenaline and serotonin reuptake Inhibition of serotonin-selective reuptake Inhibition of noradrenaline-selective reuptake Inhibition of mixed noradrenaline and serotonin reuptake Inhibition of monoamine oxidase A (MAOA). Inhibition of MAOB does not have antidepressant effects Lithium has many molecular actions (for example, inhibition of phosphatidylinositol phosphatases, adenylyl cyclases, glycogen synthase kinase (and G proteins) but which of its actions is responsible for its antimanic and antidepressant effects is unknown Unknown. Although these drugs have purported monoamine-based mechanisms (for example, bupropion inhibits dopamine reuptake, mirtazapine is an beta-2-adrenergic receptor antagonist and tianeptine an activator of monoamine reuptake), these actions are not necessarily the mechanisms that underlie the drugs’ therapeutic benefit Imipramine, desipramine Fluoxetine, citalopram Atomoxetine, reboxetine Venlafaxine, duloxetine Tranylcypromine, phenelzine Bupropion, mirtazapine, tianeptine Non-medication Electroconvulsive therapy (ECT) Magnetic stimulation Vagal nerve stimulation (VNS) Psychotherapies Deep brain stimulation General brain stimulation General brain stimulation? A magnetic field is thought to affect the brain by inducing electric currents and neuronal depolarization Unknown Exact mechanism is uncertain, but is thought to involve learning new ways of coping with problems In severely ill patients, stimulation of a region of the cingulate cortex found to function abnormally in brain imaging scans reportedly has antidepressant effects84 Cognitive-behavioural therapy, interpersonal therapy Table 1: Current treatments in MDD (Bertono & Nestler,2006). Other treatments Electroconvulsive therapy (ECT) is a highly effective treatment for MDD and in some cases, it may have a more rapid onset of action than drug treatments. However, it is used in conditions where pharmacotherapy has failed or when rapid antidepression effect is needed. Only problem with this treatment is the risk of anesthesia and neuromuscular paralysis and tolerability. There may also be postictal confusion and short-term memory difficulties (Bhalla & Aronson, 2006). Transcranial magnetic stimulation is in investigational changes for the treatment of MDD. The advantages of this form of therapy are it has the benefits of ECT without the side effects of ECT. Other non-pharmacological treatments are light therapy and vagal nerve stimulation (Bhalla & Aronson, 2006). Adjuncts to pharmacological treatment Dietary restrictions are necessary only if the patient is on MAOIs. Foods like soy sauce, aged chicken or beef liver, aged cheese, fava beans, air-dried sausage and similar meats, pickled or cured meat or fish, overripe fruit, canned figs, raisins, avocados, yogurt, sour cream, meat tenderizer, yeast extracts, caviar, shrimp paste and beer and wine are avoided when on MAOI (Bhalla & Aronson, 2006). Appropriate physical activity, exercise and stress reduction fasten recovery in MDD (Bhalla & Aronson, 2006). Ethical and legal issues As for any other mental illness, treatment of depression may involve a number of ethical and legal issues. Most of the legal issues pertain to involuntary hospitalization of patients who are at risk for suicide or who are severely crippled that they can no longer take care of themselves. However, there are legal protections of patients rights against unwillful admissions and anybody admitting a patient with depression must be ware of these policies. The burden of proof is on the treating physician who has to prove the indications for admissions. In certain countries, antidepressants cannot be given to the patient against his will and if at all it needs to be given, will need legal certification. Also, there may be insurance policies which affect the treatment. Insurance companies have there own definitions for admissions and they may cover only some psychiatric medications and a limited number of sessions of treatment (Elkin, 1999). Research There is a need for faster acting, safer and more effective treatments as far as depression is concerned (Berteno and Nestler, 2006). Research is on the way to discover drugs which act via non-monoamine systems. The difficulty faced by researchers is to get funds and animal models for this research and also to establish an animal model that fully capitulates the human form of depression (Berteno and Nestler, 2006). Some new drugs which are being considered are opioid receptor antagonists, CB-I cannabinoid receptor agonists or antagonists, cytokines, melatonin receptor agonists, galanin, neuropeptide Y, histone deacetylase inhibitors (Berteno and Nestler, 2006). Conclusion MDD is a common mental illness which causes significant incapacitation. The prevalence in females is twice as much in males. The etiologic factors are psychological, genetic and environmental. It is hereditary and can run in families. So far, no single gene has been identified which can be attributed to MDD. Those propagating epigenetic factors have attributed genetic changes to ‘endophytes’. Treatment is actually effective but induces remission in only 50% of cases. The treatment is either pharmacological or in the form of psychotherapy or both. The pharmacology treatment is mainly based on amine-hypothesis. Psychotherapy is reserved mainly for mild cases or those who have achieved remission through medicines and need only maintenance treatment. References Anderson, A.D., Oquendo, M.A., Parsey, R.V., Milak, M,S.,Campbell, C., & Mann, J.J. (2004). Regional brain responses to serotonin in major depression. Journal of affective disorders, 82(3), 411-417. Bertono, O. & Nestler, E.J. (2006). New approaches to antidepressant drug discovery: beyond monoamines. Nature Reviews – Neuroscience, 7, 137-151. Bhalla, R.N., & Aronson, S.C. (2006). eMedicine from WebMD. Retrieved on November 24th 2007 from http://www.emedicine.com/med/topic532.htm Bourin, M., David, D.J., Jolliet, P., & Gardier, A. (2002). Mechanism of action of antidepressants and therapeutic perspectives. 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